Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors
By Shaomin Li, M. Jin, Thomas Koeglsperger, Nina E. Shepardson, G. Shankar, D. Selkoe. Journal of Neuroscience, 2011
644 citations recorded by the source corpus.
In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells, AD cortex, or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors ifenprodil and Ro 25-6981. Soluble Aβ enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor dl-threo-β-benzyloxyaspartic acid. Downstream, an Aβ-mediated rise in p38 mitogen-activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.
Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology
View Paper: https://www.semanticscholar.org/paper/7ec5886ef0bc927ed23c8ff196763292e43bfaa5
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Citations in the corpus
- The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy (2016, background): “Data obtained from combined studies of electrophysiology, biochemistry, and immunohistochemistry showed that soluble Aβ oligomers, even at very low molecular concentration, inhibit LTP by increasing NMDA response through NR-2B containing NMDA-receptors (Li et al., 2011).”
- Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model (2012, background): “An alternative interpretation of our results is that synaptic, network, cognitive, and behavioral dysfunctions result from parallel processes triggered by a similar upstream mechanism that is blocked by LEV, for example, glutamate spillover leading to overactivation of extrasynaptic NMDA receptors, ”
- Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “Furthermore, AβOs destroy Glurecycling at the synapse by increasing glutamate release, reducing glutamate uptake and impairing glutamate transporters, which causes the overactivation of extrasyaptic NMDARs, ultimately leading to LTP suppression, LTD enhancement, and synaptic loss.(80) α-Amino-3-hydr”